N-phenylalkyl substituted α-amino carboxamide derivatives and process for their preparation

ABSTRACT

N-phenylalkyl substituted α-amino carboxamide derivatives of formula (I) ##STR1## wherein R is C 1  -C 8  alkyl, C 3  -C 8  cycloalkyl, furyl, thienyl, pyridyl or unsubstituted or substituted phenyl; A is a --(CH 2 ) m  -- or --(CH 2 ) p  --X--(CH 2 ) q  -- group wherein X is --O--, --S-- or --NR 4  --; R 1 , R 2 , R 3 , R&#39; 3 , R 4 , n, m, p and q are as herein defined; and each of R 5  and R 6  is independently hydrogen or C 1  -C 6  alkyl, and the pharmaceutically acceptable salts thereof, are active on the central nervous system and can be used as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic and/or hypnotic agents in mammals.

This is a divisional of application Ser. No. 08/065,888 filed on May 25,1993 (now U.S. Pat. No. 5,391,577), which is a divisional of applicationSer. No. 07/646,596, filed on Jan. 25, 1991 (now U.S. Pat. No.5,236,957) which was filed as International Application No.PCT/EP90/00841 on May 25, 1990.

The present invention relates to N-phenylalkyl substituted α-aminocarboxamide derivatives, to their use as therapeutic agents, to aprocess for their preparation and to pharmaceutical compositionscontaining them.

Other N-substituted α-amino carboxamide derivatives are known as havingpharmacological properties, for instance those described by Britishpatent No. 1140748. The compounds according to this prior art documentare useful in the treatment and prophylaxis of such diseases as coronaryartery disease and atherosclerosis; moreover they are useful in thetreatment of inflammatory conditions such as rheumatoid arthritis.

Further substituted amine acid derivatives are known as enkephalinaseinhibitors, analgesics and hypotensives from EP-A-0038758.

Still other substituted glycine and alanine derivatives are disclosed byU.S. Pat. No. 4,049,663. The compounds according to this document haveutility as oral analgesics.

It has now been found that N-phenylalkyl substituted α-amino carboxamidederivates of general formula (I), as herein defined, and thepharmaceutically acceptable salts thereof are active as anti-epileptic,anti-Parkinson, neuroprotective, antidepressant, antispastic, and/orhypnotic agents.

Accordingly the present invention relates, as a first object, to the useof a compound of formula (I), as herein defined, or a pharmaceuticallyacceptable salt thereof, as an anti-epileptic, anti-Parkinson,neuroprotective, antidepressant, antispastic, and/or hypnotic agent andto the use of a compound of formual (I), or a pharmaceuticallyacceptable salt thereof, in the preparation of a pharmaceuticalcomposition for use as an anti-epileptic, anti-Parkinson,neuroprotective, antidepressant, antispastic and/or hypnotic agent.

The compounds of formula (I) have the following general formula:##STR2## wherein R is C₁ -C₈ alkyl; a C₃ -C₈ cycloalkyl, furyl, thienylor pyridyl ring; or a phenyl ring unsubstituted or substituted by 1 to 4substituents independently chosen from halogen, C₁ -C₆ alkyl, C₁ -C₆alkoxy and trifluoromethyl;

A is a --(CH₂)_(m) -- or --(CH₂)_(p) --X--(CH₂)_(q) -- group, wherein mis an integer of 1 to 4, one of p and q is zero and the other is zero oran integer of 1 to 4 and X is --O--, --S-- or --NR₄ -- in which R₄ ishydrogen or C₁ -C₄ alkyl;

n is zero or 1;

each of R₁ and R₂, independently, is hydrogen or C₁ -C₄ alkyl;

R₃ is hydrogen, C₁ -C₄ alkyl unsubstituted or substituted by hydroxy orby a phenyl ring optionally substituted by 1 to 4 substituentsindependently chosen from halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy andtrifluoromethyl;

R'₃ is hydrogen; or R₃ and R'₃ taken together with the adjacent carbonatom form a C₃ -C₆ cycloalkyl ring;

each of R₅ and R₆, independently, is hydrogen or C₁ -C₆ alkyl; andwherein when R is C₁ -C₆ alkyl, then A is a --(CH₂)_(p) --X--(CH₂)_(q)-- group in which p and q are both zero and X is as defined above.

These compounds and their salts are hereafter referred to as the "activecompounds" and as the "compounds of the invention".

The present invention includes all the possible optical isomers of thecompounds of formula (I) and their mixtures, as well as the metabolitesof the compounds of formula (I). The present invention also includeswithin its scope pharmaceutically acceptable bioprecursors and prodrugsof the compounds of formula (I), i.e. compounds, which have a formuladifferent to formula (I), but which nevertheless are directly orindirectly converted in vivo into a compound of formula (I) uponadministration to a human being.

Pharmaceutically acceptable salts of the compounds of formula (I)include acid addition salts with inorganic acids, e.g. nitric,hydrochloric, hydrobromic, sulphuric, perchloric, and phosphoric acid,or organic acids, e.g. acetic, propionic, glycolic, lactic, oxalic,malonic, malic, tartaric, citric, benzoic, cinnamic, mandelic,methanesulfonic and salicylic acids.

The alkyl, alkylamino, alkylthio and alkoxy groups may be branched orstraight chain groups. When R₅ and R₆ are both alkyl groups, the alkylgroup for R₅ may be same as or different from the alkyl group for R₆. Ahalogen atom is preferably fluorine, chlorine or bromine, in particularfluorine or chlorine.

A C₁ -C₈ alkyl group is preferably a C₁ -C₆ alkyl group.

A C₁ -C₆ alkyl group is preferably a C₁ -C₄ alkyl group.

A C₁ -C₄ alkyl group is e.g. methyl, ethyl, propyl, isopropyl, butyl ortert.butyl, preferably it is methyl or ethyl.

A C₁ -C₆ alkoxy group is e.g. methoxy, ethoxy, propoxy, isopropoxy,butoxy or tert.butoxy, preferably it is methoxy or ethoxy.

A C₃ -C₈ cycloalkyl group is preferably a cyclopentyl, cyclohexyl orcycloheptyl group.

A C₃ -C₆ cycloalkyl ring is preferably a cyclopropyl or cyclopentylring.

A thienyl ring is for instance a 2- or 3-thienyl ring.

A pyridyl ring is for instance a 2-, 3- or 4, in particular a 3-pyridylring.

A furyl ring is for instance a 2- or 3-furyl ring.

A substituted phenyl ring is preferably substituted by one or twosubstituents chosen independently from halogen, C₁ -C₄ alkyl andtrifluoromethyl.

When in a --(CH₂)_(m) --, --(CH₂)_(p) -- or --(CH₂)_(q) -- group m, pand/or q is higher than 1, then such group may be a branched or straightalkylene chain. A (CH₂)_(m) -- group is for instance a --CH(R₁₄)-- groupin which R₁₄ is hydrogen or C₁ -C₃ alkyl, or it is a --CH₂ --CH₂ -- or--CH₂ --CH₂ --CH₂ -- group.

A C₁ -C₄ alkyl group substituted by hydroxy is preferably ahydroxymethyl or 1-hydroxyethyl group.

A C₁ -C₄ alkyl group substituted by a phenyl ring is preferably a benzylor phenethyl group.

m is preferably 1 or 2.

Each of p and q, being an integer of 1 to 4, it is preferably 1 or 2.

Preferred compounds of the invention are the compounds of formula (I),wherein

R is a phenyl ring unsubstituted or substituted by one or twosubstituents independently chosen from halogen, C₁ -C₄ alkyl andtrifluoromethyl

A is a --(CH₂)_(m) -- or --(CH₂)_(p) --X--(CH₂)_(q) -- group, wherein mis 1 or 2, one of p and q is zero and the other is zero, 1 or 2, and Xis --O--, --S-- or --NH--;

n is zero or 1;

each of R₁ and R₂, independently, is hydrogen or C₁ -C₄ alkyl;

R₃ is hydrogen or C₁ -C₄ alkyl optionally substituted by hydroxy;

R'₃ is hydrogen;

each of R₅ and R₆ is independently hydrogen or C₁ -C₄ alkyl; and thepharmaceutically acceptable salts thereof.

More preferred compounds of the invention are the compounds of formula(I), wherein

R is phenyl ring unsubstituted or substituted by halogen;

A is a --(CH₂)_(m) -- or --(CH₂)_(p) --X--(CH₂)_(q) -- group, wherein mis 1 or 2;

one of p and q is zero and the other is zero or 1 and X is --O--, --S--or --NH--;

n is zero;

R is hydrogen;

R₂ is hydrogen or C₁ -C₄ alkyl;

R₃ is hydrogen or C₁ -C₂ alkyl optionally substituted by hydroxy;

R'₃ is hydrogen;

each of R₅ and R₆ independently is hydrogen or C₁ -C₄ alkyl;

and the pharmaceutically acceptable salts thereof.

Examples of particularly preferred compounds of the invention are thefollowing:

2-(4-benzyloxybenzyl)aminopropionamide;

2- 4-(2-chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide;

2- 4-(2-chlorobenzyloxy)benzyl!aminopropionamide;

2- 4-(3-fluorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide:

2-(4-benzylaminobenzyl!aminopropionamide;

2- 4-(3-fluorobenzyloxy)benzyl!aminopropionamide;

2- 4-(2-fluorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide;

2- N-(4-benzylbenzyl)-N-methyl!aminopropionamide;

2- 4-(3-chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide;

2-(4-benzyloxybenzyl)amino-3-hydroxy-N-methylpropionamide;

2- 4-(3-chlorobenzyloxy)benzyl!aminopropionamide;

2- N- 4-(3-chlorobenzyloxy)benzyl!-N-methyl!aminoacetamide;

2- 4-(3-chlorobenzyloxy)benzyl!amino-N-methylacetamide;

2-(4-phenyloxybenzyl)amino-3-hydroxy-N-methylproprionamide;

2-(4-benzylbenzyl)aminopropionamide;

2- 4-(2-phenylethyl)benzyl!aminopropionamide;

2-(4-phenyloxymethylbenzyl)aminopropionamide;

2-(4-benzylthiobenzyl!aminopropionamide;

2- 4-(2-chlorobenzyloxy)benzyl!amino-N-methylpropionamide;

2-(4-benzyloxybenzyl)amino-N-methylpropionamide;

2- 4-(3-chlorobenzyl)-oxybenzyl!aminoacetamide;

if the case, either as single (S) or (R) isomers or as a mixturethereof; and the pharmaceutically acceptable salts thereof. Byevaluating the prior art references cited above, it appears clearly thatsome compounds, falling within the general formula (I) above, areembraced by the general formulae of some of such prior art documents,but therein not specifically mentioned; whereas other compounds ofgeneral formula (I) are not covered by the foregoing prior artdocuments.

A selected class of active compounds of formula (I) are those of formula(Ia) ##STR3## wherein R₇ is C₁ -C₈ alkyl; a C₃ -C₈ cycloalkyl, furyl,thienyl or pyridyl ring; or a phenyl ring unsubstituted or substitutedby 1 to 4 substituents independently chosen from halogen, C₁ -C₆ alkyl,C₁ -C₆ alkoxy and trifluoromethyl;

Z is a --(CH₂)_(r) -- or --(CH₂)_(s) --Y--(CH₂)_(t) -- group wherein ris an integer of 1 to 4, one of s and t is zero and the other is zero oran integer of 1 to 4, and Y is --O--, --S-- or --NR₁₃ -- in which R₁₃ ishydrogen or C₁ -C₄ alkyl;

v is zero or 1;

each of R₈ and R₉, independently, is hydrogen or C₁ -C₄ alkyl;

R₁₀ is hydrogen, C₁ -C₄ alkyl unsubstituted by hydroxy or by a phenylring optionally substituted by 1 to 4 substituents independently chosenfrom halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy and trifluoromethyl;

R'₁₀ is hydrogen; or R₁₀ and R'₁₀ taken together with the adjacentcarbon atom form a C₃ -C₆ cycloalkyl ring;

each of R₁₁ and R₁₂, independently, is hydrogen or C₁ -C₆ alkyl; and thepharmaceutically acceptable salts thereof;

and wherein a) when R₇ is C₁ -C₈ then Z is a --(CH₂)_(s) --Y--(CH₂)_(t)-- group in which both of s and t are zero and Y is as defined above;and wherein b) when R₇ is C₁ -C₈ alkyl and, at the same time, Z is a--(CH₂)_(s) --Y--(CH₂)_(t) -- group in which both of s and t are zeroand Y is --O--, R₁₀ is hydrogen or C₁ -C₄ alkyl; R'₁₀ is hydrogen, orR₁₀ and R'₁₀ taken together with the adjacent carbon atom form a C₃ -C₆cycloalkyl ring and v, R₉, R₁₁ and R₁₂ are as defined above, then R₈ isC₁ -C₄ alkyl; and wherein c) when Z is a group --(CH₂)_(s)--Y--(CH₂)_(t), in which s, t and Y are as defined above, and at thesame time R₇ is a furyl, thienyl or pyridyl ring or a phenyl ringunsubstituted or substituted by 1 or 2 substituents chosen from halogen,C₁ -C₆ alkyl, C₁ -C₆ alkoxy and trifluoromethyl, R₁₀ is hydrogen or C₁-C₄ alkyl, R'₁₀ is hydrogen, and v, R₈ and R₉ are as defined above, thenat least one of R₁₁ and R₁₂ is other than hydrogen; and wherein d) whenR₇ is phenyl unsubstituted or substituted by 1 to 4 substituents chosenfrom halogen and C₁ -C₆ alkyl, and at the same time Z is a --CH(R₁₄)--or --(CH₂)_(s) --Y--(CH₂)_(t) -- group, in which R₁₄ is hydrogen or C₁-C₃ alkyl, Y is --O-- or --S-- and s and t are both zero, R₈ and R₉ arehydrogen, v is zero and R₁₀, R'₁₀, R₁₁ and R₁₂ are as defined above,then R₁₀ is other than hydrogen or unsubstituted C₁ -C₄ alkyl.

The compounds of general formula (Ia) and their pharmaceuticallyacceptable salts, which are new, are also an object of the presentinvention. A further object of the present invention is to provide apharmaceutical composition containing as active principle a compound offormula (Ia) or a pharmaceutically acceptable salt thereof.

The preferred values of the substituents R, A, R₁, R₂, R₃, R'₃, R₅ andR₆ occurring in formula (I), given above, apply also to thecorresponding substituents R₇, Z, R₈, R₉, R₁₀, R'₁₀, R₁₁ and R₁₂occurring in formula (Ia). In particular analogously, when in a--(CH₂)_(r) --, --(CH₂)_(s) -- or --(CH₂)_(t) -- group r, s and/or t ishigher than 1, such group may be a branched or straight alkylene chain.A --(CH₂)_(r) -- group is similarly for instance a --CH(R₁₄)-- group inwhich R₁₄ is as defined above or a --CH₂ --CH₂ -- or --CH₂ --CH₂ --CH₂-- group.

Preferred compounds of formula (Ia), as defined above, are those wherein

R₇ is a phenyl ring unsubstituted or substituted by one or twosubstituents independently chosen from halogen, C₁ -C₄ alkyl andtrifluoromethyl; Z is a --(CH₂)_(r) -- or --(CH₂)_(s) --Y--(CH₂)_(t)group wherein r is 1 or 2, one of s and t is zero and the other is zero,1 or 2, and Y is --O--, --S-- or --NH--;

v is zero or 1;

each of R₈ and R₉, independently, is hydrogen or C₁ -C₄ alkyl;

R₁₀ is hydrogen or C₁ -C₄ alkyl optionally substituted by hydroxy; R'₁₀is hydrogen;

each of R₁₁ and R₁₂ is independently hydrogen or C₁ -C₄ alkyl;

and the pharmaceutically acceptable salts thereof; and wherein a) when Zis a group --(CH₂)_(s) --Y--(CH₂)_(t) -- in which s, t and Y are asdefined above and at the same time R₇ is a phenyl ring as defined above,R₁₀ is hydrogen or unsubstituted C₁ -C₄ alkyl, v, R₈ and R₉ are asdefined above, then at least one of R₁₁ and R₁₂ is other than hydrogen;and wherein b) when R₇ is a phenyl ring unsubstituted or substituted byone or two substituents chosen from halogen and C₁ -C₄ alkyl, and at thesame time Z is a --CH(R₁₄)-- or --(CH₂)_(s) --Y--(CH₂)_(t) -- group inwhich R₁₄ is hydrogen or C₁ -C₃ alkyl, Y is --O-- or --S-- and s and tare both zero, R₈ and R₉ are hydrogen, v is zero and R₁₁ and R₁₂ are asdefined above, then R₁₀ is C₁ -C₄ alkyl substituted by hydroxy.

Preferred examples of specific compounds of formula (Ia) are thefollowing:

2- 4-(2-chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide;

2- 4-(3-fluorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide:

2- 4-(2-fluorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide;

2- N-(4-benzylbenzyl)-N-methyl!aminopropionamide;

2- 4-(3-chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide;

2-(4-benzyloxybenzyl)amino-3-hydroxy-N-methylpropionamide;

2- 4-(3-chlorobenzyloxy)benzyl!amino-N-methylacetamide;

2-(4-phenyloxybenzyl)amino-3-hydroxy-N-methylpropionamide;

2- 4-(2-phenylethyl)benzyl!aminopropionamide;

2- 4-(2-chlorobenzyloxy)benzyl!amino-N-methylpropionamide;

2-(4-benzyloxybenzyl)amino-N-methylpropionamide;

if the case, either as single (S) or (R) isomers or as a mixture thereofand the pharmaceutically acceptable salts thereof.

None of the compounds of formula (I) herein specifically mentioned assingle chemical entity, but embraced by the general formulae of theprior art documents, has ever been specifically mentioned before in anyof them. These new chemical compounds and the pharmaceuticallyacceptable salts thereof are a further object of the present invention.

Examples of such new compounds are the following:

2-(4-benzyloxybenzyl)aminopropionamide;

2- 4-chlorobenzyloxy)benzyl!aminopropionamide;

2-(4-benzylaminobenzyl)aminopropionamide;

2- 4-(3-fluorobenzyloxy)benzyl!aminopropionamide;

2- 4-(3-chlorobenzyloxy)benzyl!aminoacetamide;

2- N- 4-(3-chlorobenzyloxy)benzyl!-N-methyl!aminoacetamide;

2-(4-benzylbenzyl)aminopropionamide;

2-(4-phenyloxymethylbenzyl)aminopropionamide;

2-(4-benzylthiobenzyl))aminopropionamide;

if the case, either as single (S) or (R) isomers or as a mixture thereofand the pharmaceutically acceptable salts thereof.

These new chemical compounds can be represented by the following generalformula (Ib) ##STR4## wherein R'₇ is a phenyl ring unsubstituted orsubstituted by a halogen atom;

Z' i s a --(CH₂)_(r) -- or --(CH₂)_(s) --Y--(CH₂)_(t) -- group in whichr is 1 one of s and t is zero and the other is zero or 1, and Y is --O----S-- or --NHR--

R'₈ is hydrogen;

w is zero;

R'₉ is hydrogen or methyl;

R"₁₀ is hydrogen or methyl;

R'₁₁ and R'₁₂ are hydrogen.

The compounds of formula (Ib) and the pharmaceutically acceptable saltsthereof are a further object of the present invention.

An object according to this invention is also to provide apharmaceutical composition containing as active principle a compound offormula (Ib) or a pharmaceutically acceptable salt thereof; inparticular a compound selected from the group consisting of

2-(4-benzyloxybenzyl)aminopropionamide;

2- 4-(2-chlorobenzyloxy)benzyl!aminopropionamide;

2-(4-benzylaminobenzyl)aminopropionamide;

2- 4-(3-fluorobenzyloxy)benzyl!aminopropionamide;

2- 4-(3-chlorobenzyloxy)benzyl!aminopropionamide;

2- N- 4-(3-chlorobenzyloxy)benzyl!-N-methyl!aminoacetamide;

2- 4-(3-chlorobenzyloxy)benzyl!aminoacetamide;

2-(4-benzylbenzyl)aminopropionamide;

2-(4-phenyloxymethylbenzyl)aminopropionamide;

2-(4-benzylthiobenzyl)aminopropionamide;

if the case, either as single (S) or (R) isomers or as a mixturethereof, or a pharmaceutically acceptable salt thereof.

The N-phenylalkyl substituted α-amino carboxamide derivatives of formula(I) can be prepared by the analogy process below. The derivatives offormula (Ia) can be prepared in the same way using starting compounds(IIa) to (IXa), (X) and (XI) in which symbols R₇ to R₁₂, R'₁₀, Z and vreplace symbols R, R₁ to R₃, R₅, R₆, R'₃, A and n respectively incompounds (II) to (IX). The derivatives of formula (Ib) can also beprepared in the same way using starting compounds (IIb) and (IVb) to(IXb), (X) and (XI) in which symbols R'₇ to R'₉, R"₁₀, R'₁₁, R'₁₂, Z'and w replace symbols R, R₁ to R₃, R₅, R₆, A and n respectively incompounds (II) and (IV) to (IX) and the symbol corresponding to R'₃ isH. The analogy process for the preparation of the derivatives of formula(I) comprises:

a) reacting a compound of formula (II) or (III), respectively, ##STR5##wherein R, R₁ and A are as defined above, with a compound of formula(IV) ##STR6## wherein R₂, R₃ and R'₃ are as defined above, and R₅ andR₆, being as defined above, are not both a C₁ -C₆ alkyl group, thusobtaining a compound of the invention wherein n is zero or 1,respectively, and R₅ and R₆, being as defined above, are not both C₁ -C₆alkyl; or

b) reacting a compound of formula (V) or an alkyl ester thereof ##STR7##wherein R, A, R₁, R₂, R₃, R'₃ and n are as defined above, with an amineof formula (VI) ##STR8## wherein R₅ and R₆ are as defined above; or

c) reacting a compound of formula (VII) ##STR9## wherein R, A, R₁, n andR₂ are as defined above, with a compound of formula (VIII) ##STR10##wherein W is a halogen atom and R₅ and R₆ are as defined above; thusobtaining a compound of the invention wherein R₃ and R'₃ are bothhydrogen; or

d) reacting a compound of formula (IX) ##STR11## wherein R, A, R₁, n,R₃, R'₃, R₅ and R₆ are as defined above, with a compound of formula (X)or (XI)

    R".sub.9 --W                                               (X)

    R"'.sub.9 --CHO                                            (XI)

wherein W is a halogen atom; R"₉ is C₁ -C₄ alkyl and R"'₉ is hydrogen orC₁ -C₃ alkyl, thus obtaining a compound of the invention in which R₂ isC₁ -C₄ alkyl; and, if desired, converting a compound of the inventioninto another compound of the invention and/or, if desired, converting acompound of the invention into a pharmaceutically acceptable saltand/or, if desired, converting a salt into a free compound and/or, ifdesired, separating a mixture of isomers of compounds of the inventioninto the single isomers.

All the processes described hereabove are analogy processes and can becarried out according to well known methods in organic chemistry.

The reaction of a compound of formula (II) or (III) with a compound offormula (IV) is a reductive amination reaction which can be carried outaccording to well known methods. According to a preferred embodiment ofthe invention it may be performed under nitrogen atmosphere, in asuitable organic solvent, such as an alcohol, e.g. a lower alkanol, inparticular methanol, or in acetonitrile, at a temperature ranging fromabout 0° C. to about 40° C., in the presence of a reducing agent, themost appropriate being sodium cyanoborohydride. Occasionally molecularsieves can be added to the reaction mixture for facilitating thereaction.

An alkyl ester of a compound of formula (V) is e.g. a C₁ -C₆ alkyl estersuch as a C₁ -C₄ alkyl ester and, in particular a methyl, ethyl orpropyl ester, which may be unsubstituted or substituted by a phenyl ringoptionally substituted by a nitro group.

Preferably an alkyl ester of a compound of formula (V) is used.

The reaction of a compound of general formula (V) or of an alkyl esterthereof, with an amine of formula (VI) can be performed using an excessof the amine, eventually in the presence of water or of an organicsolvent, such as dimethylformamide. The temperature of the reaction mayrange from about 20° C. to about 100° C.

In a compound of formula (VIII) W is preferably bromine or chlorine. Thereaction of a compound of general formula (VII) with a compound ofgeneral formula (VIII) can be carried out in a suitable organic solvent,such as an alcohol, e.g. ethanol, or in dimethylformamide, at atemperature ranging from about 40° C. to about 140° C. in the presenceof a suitable acid acceptor e.g. anhydrous potassium carbonate.

In a compound of formula (X) the halogen W is preferably iodine. Thealkylation reaction of a compound formula (IX) with a compound offormula (X) can be carried out in a suitable organic solvent, such as analcohol, e.g. methanol, ethanol or isopropanol, in particular inmethanol, at a temperature ranging from about 0° C. to about 50° C.

The alkylation reaction of a compound of formula (IX) with an aldehydeof formula (XI) can be carried out in a suitable organic solvent, suchas an alcohol, e.g. methanol, or acetonitrile in the presence of asuitable reducing agent, such as sodium cyanoborohydride, at atemperature ranging from about 0° C. to about 30° C.

A compound of the invention can be converted, as stated above, intoanother compound of the invention by known methods. Process-variant d)above may be regarded as an example of optional conversion of a compoundof the invention into another compound of the invention.

Also the optional salification of a compound of the invention as well asthe conversion of a salt into the free compound and the separation of amixture of isomers into the single isomers may be carried out byconventional methods.

The compounds of formulae (II), (III), (IV), (V), (VI), (VII), (VIII),(X) and (XI) are known compounds or can be obtained by known methodsfrom known compounds.

For instance, the carboxylic acids of formula (V) and the alkyl estersthereof can be obtained as described in GB-A-1140748 (Derwent 30027F).An acid of formula (V), in which n is zero or 1, can be obtained also byreacting a compound of formula (II) or (III), respectively, as definedabove, with a compound of formula (XII) ##STR12## wherein R₂, R₃ and R'₃are as defined above.

The reaction of a compound of formula (XII) with a compound of formula(II) or (III) may be carried out by following the same procedurepreviously described as to process-variant a). The compounds of formula(IX) are compounds according to the present invention wherein R₂ ishydrogen and can be obtained by process variants a) and b) hereindescribed.

The compounds of formula (XII) are known compounds or can be obtained byknown methods.

When in the compounds of the present invention and in theintermediate-products thereof, groups are present, which need to beprotected before submitting them to the hereabove illustrated reactions,they may be protected before being reacted and then deprotected,according to methods well known in organic chemistry.

The intermediate compounds, according to the processes herein describedfor the preparation of the compounds of the invention, may be either inthe form of a single isomer or as a mixture thereof. Preferably they arein the form of a single isomer.

PHARMACOLOGY

The compounds of the invention and the selected classes thereof offormula (Ia) and (Ib), as herein defined, are active on the centralnervous system (CNS) and can be used in therapy, for example asantiepileptics, in the treatment of Parkinson's disease and asneuroprotective agents in degenerative processes associated with normalageing or pathological situations, such as brain ischemia; they can alsobe used as antidepressants, hypnotics and antispastic agents.

The activity on the CNS of the compounds of the invention was evaluatedon the basis of pharmacological methods, such as, for example, theantagonism of convulsions and lethality induced by intravenous injectionof bicucculine in mice (Antiepileptic Drug, D. M. Woodbury et al. eds.,2nd edition, Raven Press, New York, 1982), or the antagonism ofconvulsions induced in mice by subcutaneous injection of3-mercaptopropionic acid (W. Lo/ scher, Biochem. Pharmacol., 28;1397-1407, 1979).

Accordingly in following Tables 1 and 2, the doses which protect 50% ofthe mice (i.e. ED₅₀) from lethality and tonic convulsions induced bybicucculine and 3-mercaptopropanoic acid, respectively, are given for arepresentative group of compounds according to the present invention.

                  TABLE 1    ______________________________________    Antagonism of bicucculine-induced lethality in mice.    Drugs were given orally 1 h before bicucculine    (0.6 mg/kg, i.v.)     ##STR13##    In-    ternal                                     ED.sub.50    code                                       mg/kg,    (FCE) R-A-          R.sub.2                               R.sub.3                                      R.sub.5                                           *   p.o.    ______________________________________    25989 m.chlorobenzyloxy                        H      H      H        190    26312 m.chlorobenzyloxy                        H      CH.sub.3                                      H    R   50    26358 benzyloxy     H      CH.sub.2 OH                                      CH.sub.3                                           S   16    26359 m.chlorobenzyloxy                        H      CH.sub.2 OH                                      CH.sub.3                                           S   29    26502 o.chlorobenzyloxy                        H      CH.sub.2 OH                                      CH.sub.3                                           S   27    26550 benzyloxy     H      CH.sub.3                                      H    S   15    26649 o.fluorobenzyloxy                        H      CH.sub.2 OH                                      CH.sub.3                                           S   12    26650 m.fluorobenzyloxy                        H      CH.sub.2 OH                                      CH.sub.3                                           S   25    26700 o.chlorobenzyloxy                        H      CH.sub.3                                      H    S   17    26723 benzyl        H      CH.sub.3                                      H    S   16    26743 m.fluorobenzyloxy                        H      CH.sub.3                                      H    S   29    26749 benzylamino   H      CH.sub.3                                      H    S    9    26762 benzyl        CH.sub.3                               CH.sub.3                                      H    S   54          Valproate                            401    ______________________________________     *absolute configuration

                  TABLE 2    ______________________________________    Antagonism of 3-mercaptopropionic acid (MPA) induced    tonic convulsions in mice; drugs were given orally    1 h before MPA (60 mg/kg s.c.)    Internal code ED 50 (mg/kg, p.o.)    ______________________________________    FCE 25989     28    FCE 26312     10    FCE 26358     43    FCE 26359     29    FCE 26502     16    FCE 26550     13    Valproate     302    ______________________________________

The ED₅₀ data set out in tables 1 and 2 show that the compoundsaccording to the present invention are very active as antiepilepticagents. In fact ED₅₀ values largely higher than those determined for thecompounds of the invention were found with Valproate, which is a verywell known and largely used antiepileptic drug.

The internal FCE codes occurring in Tables 1 and 2 identify thefollowing compounds (enclosed in brackets is the internal FCE code):

25989! 2- 4-(3-chlorobenzyloxy)benzyl!aminoacetamide;

26550! (S)-2-(4-benzyloxybenzyl)aminopropionamide;

26502! (S)-2-4-(2-chlorobenzyloxybenzyl!amino-3-hydroxy-N-methylpropionamide;

26700! (S)-2- 4-(2-chlorobenzyloxy)benzyl!aminopropionamide;

26650! (S)-2-4-(3-fluorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide;

26749! (S)-2-(4-benzylaminobenzyl)aminopropionamide;

26743! (S)-2- 4-(3-fluorobenzyloxy)benzyl!aminopropionamide;

26649! (S)-2-4-2-fluorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide;

26762! (S)-2- N-(4-benzylbenzyl)-N-methyl!aminopropionamide;

26359! (S)-2-4-(3-chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide;

26358! (S)-2-(4-benzyloxybenzyl)amino-3-hydroxy-N-methylpropionamide;

26312! (R)-2- 4-(3-chlorobenzyloxy)benzyl!aminopropionamide; and

26723! (S)-2-(4-benzylbenzyl)aminopropionamide.

The compounds of the invention are also potent inhibitors of monoamineoxidase (MAO). As an example, using rat liver mitochondria as the sourceof MAO and 2-phenylethylamine as substrate, a IC₅₀ value of 2×10⁻⁷ Mtoward MAO type B was found for compound FCE 25989. The activity ofbrain MAO-B has been shown to be increased with ageing as well as indegenerative disorders (for review, see M. Strolin Benedetti and P.Dosterr, Biochem. Pharmacol. 38: 555-561, 1988). The compounds of theinvention have also been shown to increase the levels of serotonin(5-HT) and of its main metabolite, 5-hydroxy-indole-3-acetic acid(5-HIAA) in various brain areas. As an example, administration (200mg/kg; p.o.) of compound FCE 25989 to mice was found to result in anincrease of 5-HT (48%) and 5-HIAA (37%) in frontal cortex.Administration of L-tryptophan, the natural bioprecursor of 5-HT and5-HIAA has been shown to be effective in the treatment of affectivedisorders and mild to moderate insomnia (for review, see B. Boman, Aust.New Zealand J Psychiatry 22: 83-97, 1988).

The toxicity of the compounds of the invention is negligible; thereforethey can be safely used in therapy. The toxicity was evaluated asfollows: nine hours food deprived mice were treated orally with singleadministration of increasing doses, then housed and normally fed. Theorientative acute toxicity (LD₅₀) was assessed on the senventh day afterthe treatment.

The compounds of the invention can be administered in a variety ofdosage forms, e.g. orally, in the form of tablets, capsules, sugar orfilm coated tablets, liquid solutions; rectally, in the form ofsuppositories; parenterally, e.g. intramuscularly or by intravenousinjection or infusion. The therapeutic regimen for the differentclinical syndromes must be adapted to the type of pathology taking intoaccount as usual, also the route of administration, the form in whichthe compound is administered and the age, weight and conditions of thesubject involved.

The oral route is employed, in general, for all conditions requiringsuch compounds. In emergency situations preference is given tointravenous injection.

For these purposes the compounds of the invention can be administeredorally at doses ranging e.g. from about 50 to about 1500 mg/day. Ofcourse, these dosage regimens may be adjusted to provide the optimaltherapeutic response.

The nature of the pharmaceutical compositions containing the compoundsof this invention in association with pharmaceutically acceptablecarriers or diluents will, of course, depend upon the desired route ofadministration.

The compositions may be formulated in the conventional manner with theusual ingredients. For example, the compounds of the invention may beadministered in the form of aqueous or oily solutions or suspensions,tablets, pills, gelatine capsules, syrups, drops or suppositories.

Thus, for oral administration, the pharmaceutical compositionscontaining the compounds of this invention are preferably tablets, pillsor gelatine capsules which contain the active substance together withdiluents, such as lactose, dextrose, sucrose, mannitol, sorbitol,cellulose; lubricants, for instance silica, talc, stearic acid,magnesium or calcium stearate, and/or polyethylene glycols; or they mayalso contain binders, such as starches, gelatine, methylcellulose,carboxymethylcellulose, gum arabic, tragacanth, polyvinylpyrrolidone;disaggregating agents, such as starches, alginic acid, alginates, sodiumstarch glycolate; effervescing mixtures; dyestuffs; sweeteners; wettingagents, such as lecithin, polysorbates, laurylsulphates; and, ingeneral, non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. Said pharmaceutical preparations may bemanufactured in known manner, for example by means of mixing,granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersions for oral administration may be e.g. syrups,emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharosewith glycerine and/or mannitol and/or sorbitol. The suspensions and theemulsions may contain as carrier, for example, a natural gum, agar,sodium alginate, pectin, methylcellulose, carboxymethylcellulose, orpolyvinyl alcohol.

The suspensions or solutions for intramuscular injections may containtogether with the active compound a pharmaceutically acceptable carrier,e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propyleneglycol, and if desired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injection or infusion may contain ascarrier, for example, sterile water or preferably they may be in theform of sterile aqueous isotonic saline solutions.

The suppositories may contain together with the active compound apharmaceutically acceptable carrier, e.g. cocoabutter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

The following examples illustrate but do not limit the invention.

EXAMPLE 1

22.4 g (0.203 mol) of glycinamide hydrochloride are suspended in 1000 mlof dry methanol and 10.2 g (0.162 mol) of sodium cyanoborohydride areadded while stirring under nitrogen. After solubilization of themixture, 50 g (0.203 mol) of 3-chlorobenzyloxybenzaldehyde are added ina single portion. The reaction mixture is stirred 8 hours at roomtemperature and then allowed to stand 16 hours. The solution is filteredand evaporated, taken up with water and extracted three times withmethylene chloride. After drying and evaporating, the crude residue ischromatographed on silica gel (eluant: chloroform/methanol/conc. NH4OH;97/3/0.3) to give 2- 4-(3-chlorobenzyloxy)benzyl!aminoacetamide which byreaction with the stoichiometric amount of gaseous HCl in ethanol istransformed into its hydrochloride (32.1 g, 46.3%, m.p.: 225°-230° C.).

Analogously, the following compounds can be obtained, starting from thecorresponding aldehyde or ketone and the appropriate α-aminoamide and,if the case, a suitable acidic agent:

(4-Benzyloxybenzyl) aminoacetamide, hydrochloride, m.p. 250° C.;

4-(3-chlorobenzyloxy)-α-methyl-benzyl!aminoacetamide, hydrochloride,m.p. 199.5°-202° C.;

(R)-2- 4-(3-Chlorobenzyloxy)benzyl!amino-3-hydroxy-propionamide, m.p.110°-110.5° C.;

(S)-2- 4-(3-Chlorobenzyloxy-benzyl!amino-3-hydroxy-propionamide, m.p.111°-113° C.;

2- 4-(3-Chlorobenzyloxy)benzyl!amino-N-methylacetamide, hydrochloride,m.p. 226°-228° C.;

(S)-2- 4-(3-Chlorobenzyloxy)benzyl!amino-N-methylpropionamide,hydrochloride; m.p. 176.5°-178.5° C.;

(S)-2- 4-(3-Chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide, m.p. 128°-130° C.;

(S)-2- 4-(3-Chlorobenzyloxy)benzyl!aminopropionamide, m.p.198.5° C.;

(S)-2-(4-Benzyloxybenzyl)amino-N-methylpropionamide, m.p. 189°-191.5° C.

(S)-2-(4-Benzyloxybenzyl)amino-3-hydroxy-N-methylpropionamide, m.p.102°-104° C.;

(R)-2- 4-(3-Chlorobenzyloxy)benzyl!aminopropionamide, hydrochloride m.p.198.5°-200° C.;

(R)-2-(4-Benzyloxybenzyl)amino-3-hydroxy-N-methylpropionamide, m.p.100°-103° C.;

(S)-2- 4-(3-Methoxybenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide, m.p. 83°-87° C.;

(S)-2- 4-(2-Chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide, m.p. 131°-134° C.;

(S)-2- 4-(4-Chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide, m.p. 139°-141° C.;

1- (4-Benzyloxybenzyl)amino!cyclopentane-1-N-methylcarboxamide,hydrochloride, m.p. 218°-221° C.;

2-(4-Benzyloxybenzyl)amino-N-methylacetamide, hydrochloride, m.p.238°-242° C.

1- (4-Benzyloxybenzyl)amino!cyclopropane-1-N-methylcarboxamide,hydrochloride, m.p. 194-200 (dec) °C.;

1- (4-Benzyloxybenzyl)amino!cyclopentane-1-carboxamide, hydrochloride,m.p. 229°-234° C.;

(S)-2-(4-Benzyloxybenzyl)aminopropionamide, m.p. 229°-232° C.;

(S)-2-(4-Benzyloxybenzyl)amino-3-methyl-N-methylbutanamide,hydrochloride, m.p. 160°-163° C.;

(R)-2-(4-Benzyloxybenzyl)amino-3-methyl-N-methylbutanamide,hydrochloride, m.p. 161°-165° C.;

(R)-2-(4-Benzyloxybenzyl) amino-3-phenyl-N-methylpropionamide, m.p.222.5°-227.5° C.;

1- (4-Benzyloxybenzyl)amino!cyclopropane-1-carboxamide,methanesulfonate, m.p. 219-228 (dec) °C.;

(R)-2-(4-Benzyloxybenzyl)aminopropionamide, hydrochloride, m.p.228°-231° C.;

(2R, 3S)-2-(4-Benzyloxybenzyl)amino-3-hydroxy-N-methylbutanamide,hydrochloride, m.p. 187.5°-191° C.;

(2S,3R)-2-(4-Benzyloxybenzyl)amino-3-hydroxy-N-methylbutanamide,hydrochloride, m.p. 187°-191° C.;

(S)-2-(4-Benzyloxybenzyl)amino-4-methyl-N-methylpentanamide,hydrochloride, m.p. 141°-144° C.;

(S)-2-(4-Benzyloxybenzyl)amino-3-hydroxy-propionamide, m.p. 128.5°-130°C.;

(R)-2-(4-Benzyloxybenzyl)amino-3-hydroxy-propionamide, m.p. 117°-122°C.;

(S)-2- 4-(2-Methylbenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide, methanesulfonate, m.p. 170°-172° C.;

(S)-2- 4-(3-Methylbenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide, methanesulfonate, m.p. 80°-82° C. (water 0.57% );

(S)-2-4-(3-Trifluoromethylbenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide,methanesulfonate, m.p. 120.5°-124° C.;

(S)-2-4-(2-Trifluoromethylbenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide,methanesulfonate, m.p. 60°-70° C. (water 1.39%);

(S)-2- 4-(2-Fluorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide,methanesulfonate, m.p. 137°-140° C.;

(S)-2- 4-(3-Fluorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide,methanesulfonate, m.p. 135°-138° C.;

(S)-2- 4-(2-Chlorobenzyloxy)benzyl!aminopropionamide, methanesulfonate,m.p. 219°-220° C.;

(S)-2- 4-(2-Chlorobenzyloxy)benzyl!amino-N-methylpropionamide,methanesulfonate, m.p. 80-90 (water 1.21%) °C.;

(R)-2- 4-(2-Chlorobenzyloxy)benzyl!amino-N-methylpropionamide,methanesulfonate, m.p. 130°-134° C.;

(R)-2- 4-(2-Chlorobenzyloxy)benzyl!aminopropionamide, methanesulfonate,m.p. 218°-221° C.;

(R)-2-(4-Benzyloxybenzyl)amino-N-methylpropionamide, methanesulfonate,m.p. 134.5°-138.5° C.;

(S)-2-(4-Phenyloxybenzyl)aminopropionamide, methanesulfonate, m.p.210°-213° C.;

(S)-2-(4-Phenyloxybenzyl)amino-3-hydroxy-N-methyl propionamide,methanesulfonate, m.p. 112°-116° C.;

(S)-2-(4-Benzylbenzyl)aminopropionamide, methanesulfonate, m.p.182°-185° C.;

(S)-2- 4-(2-phenylethyl)benzyl!aminopropionamide, methanesulfonate, m.p.235°-238° C.;

(S)-2-(4-Benzylbenzyl)amino-3-hydroxy-N-methylpropionamide,methanesulfonate, m.p. 126°-128° C.;

(S)-2-(4-Phenylethyloxybenzyl)aminopropionamide, methanesulfonate, m.p.178°-181° C.;

(S)-2-(4-Benzylthiobenzyl)aminopropionamide, methanesulfonate, m.p. 250°C.;

(S)-2-(4-Benzylthiobenzyl)amino-3-hydroxy-N-methylpropionamide,methanesulfonate, m.p. 151°-155° C.;

(S)-2-(4-phenylethylbenzyl)amino-3-hydroxy-N-methylpropionamide,methanesulfonate, m.p. 143°-146° C.;

(S)-2- 4-(2-phenylethyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide,methanesulfonate, m.p. 108°-110° C.;

(S)-2-(4-phenyloxymethylbenzyl)aminopropionamide, methanesulfonate, m.p.212°-217° C.;

(S)-2- 4-(2-Fluorobenzyloxy)benzyl!aminopropionamide, m.p. 237°-241° C.;

(S)-2- 4-(3-Fluorobenzyloxy)benzyl!aminopropionamide, m.p. 208°-212° C.;

(S)-(+)-2-(4-phenyloxymethylbenzyl)amino-3-hydroxy-N-methylpropionamide,methanesulfonate, m.p. 125°-128° C.;

(S)-2-(4-Benzylaminobenzyl)amino-3-hydroxy-N-methylpropionamide,dihydrochloride m.p. 193°-195° C.;

(S)-2-(4-Benzylaminobenzyl)aminopropionamide, dihydrochloride m.p. 173°C.;

(S)-2-(4-Benzyloxyphenetyl)aminopropionamide, methanesulfonate;

(S)-2- 4-(2-Chlorobenzyloxy)phenetyl!aminopropionamide,methanesulfonate;

2- 4-(3-Chlorobenzyloxy)-α-methyl-benzyl!aminopropionamide,methanesulfonate;

(S)-2- 4-(3-Phenylpropyloxy)benzyl!aminopropionamide, methanesulfonate;

2- (4-Benzyl)-α-methyl-benzyl!aminopropionamide, methanesulfonate;

(R)-2-(4-Benzyloxybenzyl)aminobutanamide, methanesulfonate;

(S)-2-(4-Benzyloxybenzyl)aminobutanamide, methanesulfonate;

(S)-2-(2-Benzyloxybenzyl)aminopropionamide, methanesulfonate;

(S)-2-(3-Benzyloxybenzyl)aminopropionamide, methanesulfonate;

(S)-2-(4-Cyclohexylmethylaminobenzyl)aminopropionamide, dihydrochloride;

(S)-2-(4-Cyclopropylmethylaminobenzyl)aminopropionamide,dihydrochloride;

(S)-2-(4-Phenylaminomethylbenzyl)aminopropionamide, dihydrochloride:

(S)-2-(4-Benzylaminomethylbenzyl)aminopropionamide, dihydrochloride;

(S)-2- 4-(3-Furfuryloxy)benzyl!aminopropionamide, methanesulfonate;

(S)-2- 4-(2-Furfuryloxy)benzyl!aminopropionamide, methanesulfonate;

(S)-2- 4-(3-Pyridyl)methyloxybenzyl!aminopropionamide, methanesulfonate;

(S)-2- 4-(2-Pyridyl)methyloxybenzyl!aminopropionamide, methanesulfonate;

(S)-2- 4-(4-Pyridyl)methyloxybenzyl!aminopropionamide, methanesulfonate;

(S)-2- 4-(3-Thenyloxy)benzyl!aminopropionamide, methanesulfonate; and

(S)-2- 4-(2-Thenyloxy)benzyl!aminopropionamide, methanesulfonate.

EXAMPLE 2

0.8 g (0.00298 mol) of (S)-(+)-2-(4-benzylbenzyl)aminopropionamide aredissolved in 45 ml of acetonitrile under a nitrogen stream. To thismixture, 2.98 ml (0.0149 mol) of 37% formaldehyde and 0.27 g (0.00432mol) of sodium cyanoborohydride are added at room temperature. After 40min glacial acetic acid is dropped up to neutrality of the solution. Themixture is evaporated to dryness and 40 ml of 2N KOH are added: Afterextracting with ethyl acetate, washing with N/2 KOH and then with waterand brine, the solution is dried on Na2SO4, then filtered and evaporatedto obtain a crude oil which is chromatographed on silica gel (eluantCHCl3/MeOH/conc. NH4OH; 200/3/0.2) to give 0.58 g (69%) of a colourlessoil. The product is dissolved in methanol and reacted with an equimolarquantity of oxalic acid, to obtain white crystals of (S)-2-N-(4-benzylbenzyl)-N-methyl!aminopropionamide, oxalate (m.p. 58°-64°C.).

Analogously the following compounds can be obtained, starting from thecorresponding secondary amine:

(R)-2- N-(4-Benzyloxybenzyl)-N-methyl!amino-3-hydroxy-N-methylpropionamide, m.p. 73°-77° C.;

(S)-2- N-(4-Phenyloxymethylbenzyl)-N-methyl!aminopropionamide;

(S)-2- N-(4-Benzylethylbenzyl)-N-methyl!aminopropionamide;

(S)-2-N-(4-Benzylbenzyl)-N-methyl)!amino-3-hydroxy-N-methylpropionamide;

(S)-2- N-(4-Benzylthiobenzyl)-N-methyl!aminopropionamide;

(S)-2- N-(4-Benzylaminobenzyl)-N-methyl!aminopropionamide:(NMR;δ(CDCl3):1.05 (d,3H,Me) 2.02 (s,3H,N--Me) 3.55 (q, 1H,CH--CONH2)4.20 (s,2H,ArCH2NMe) 4.28 (s,2H,ArCH2NHAr) 6.55-7.30 (m,11H,arom.+CONH2);

(S)-2-N-(4-(2-Chlorobenzyloxy)benzyl)-N-methyl!amino-3-hydroxy-N-methylpropionamide,methanesulfonate;

(S)-2-N-(4-(3-Fluorobenzyloxy)benzyl)-N-methyl!amino-3-hydroxy-N-methylpropionamide,methanesulfonate;

(S)-2-N-(4-(2-Fluorobenzyloxy)benzyl)-N-methyl!amino-3-hydroxy-N-methylpropionamide,methanesulfonate;

(S)-2- N-(4-(3-Fluorobenzyloxy)benzyl)-N-methyl!aminopropionamide,methanesulfonate; and

(S)-2- N-(4-(2-Chlorobenzyloxy)benzyl)-N-methyl!aminopropionamide,methanesulfonate.

EXAMPLE 3

33.5 g (0.149 mol) of N-benzylidene-tyramine are added to a mixture of4.45 g (0.193 mol) of sodium in 400 ml of anhydrous ethanol. Aftercooling to 0°-5° C., a solution of 3-chlorobenzylchloride (28.8 g; 0.193mol) in dry ethanol (150 ml) is dropped. After stirring 1 hour at roomtemperature, reflux is maintained for 6 hours. The hot mixture isfiltered and the solution is concentrated to dryness. The residue istaken up with 10% HCl (170 ml) and heated at 70°-75° C. for 1 hour. Thewhite solid precipitate is filtered and washed with n-hexane. Afterrecrystallization from ethanol, 31 g of4-(3-chlorobenzyloxy)phenetylamine,hydrochloride are obtained, m.p.195-200 (dec).

31 g (0.104 mol) of 4-(3-chlorobenzyloxy)phenetylamine hydrochloride aresuspended in 450 ml of anhydrous ethanol. To this mixture, 9.7 g (0.104mol) of chloroacetamide and 28.8 g (0.208 mol) of anhydrous potassiumcarbonate are added. After heating to reflux, stirring is continued for40 hours. The hot mixture is filtered, then evaporated to dryness andthe crude residue chromatographed on silica gel (eluant CHCl3/MeOH/conc.NH4OH; 97/3/0.3). The free compound obtained (20.2 g; 60.7%) is treatedwith gaseous HCl in ethanol to give a quantitative yield of thecorresponding 4-(3-chlorobenzyloxy)phenetyl!aminoacetamide,hydrochloride, m.p. 248°-251° C.

Analogously the following compound can be obtained, starting from thecorresponding primary amine:

4-(3-chlorobenzyloxy)-α-methyl-benzyl!aminoacetamide, hydrochloride,m.p. 199.5°-202° C.;

2- (4-Benzylphenylethyl!aminoacetamide; and

2- 2-(4-Benzylamino)phenylethyl!aminoacetamide;

EXAMPLE 4

7.07 g (0.066 mol) of glycine ethyl ester, hydrochloride are diluted in200 ml of dry methanol and 3.32 g (0,053 mol) of sodium cyanoborohydrideare added, while stirring under nitrogen. To this solution, 15 g (0.0608mol) of 3-chlorobenzyloxybenzaldehyde are added in a single portion.Stirring is continued for 18 hours at room temperature, the mixture isevaporated to dryness and the crude residue chromatographed on silicagel (eluant: cyclohexane/ethyl acetate; 60/40).

6.8 g (34%) of 4-(3-chlorobenzyloxy)benzyl!amino acetic acid, ethylester are obtained (m.p. 114°-115° C. as hydrochloride).

3 g (0.0090 mol) of the above ester (free base) are heated in 70 ml ofdimethylamine at 60° C. for 7 hours. The solution is allowed to standovernight at room temperature, then evaporated and the residue ispurified on silica gel (eluant: chloroform/methanol/30% N}{4OH;95/5/0.5) to afford 0.7 g (23%)of4-(3-chlorobenzyloxy)benzyl!amino-N,N-dimethylacetamide, hydrochloride(m.p. 120°-125° C.).

Analogously the following compounds can be obtained, starting from thecorresponding ethyl esters:

2-(4-Benzyloxybenzyl)amino-N,N-dimethylacetamide;

2-(4-Benzyloxybenzyl)amino-3-hydroxy-N,N-dimethylpropionamide;

2-(4-Benzylbenzyl)amino-N,N-dimethylacetamide

2-(4-Benzylaminobenzyl)amino-N,N-dimethylacetamide;

(S)-2-4-(2-Chlorobenzyloxy)benzyl!amino-3-hydroxy-N,N-dimethylpropionamide,methanesulfonate;

(S)-2-4-(3-Fluorobenzyloxy)benzyl!amino-3-hydroxy-N,N-dimethylpropionamide,methanesulfonate;

(S)-2-4-(2-Fluorobenzyloxy)benzyl!amino-3-hydroxy-N,N-dimethylpropionamide,methanesulfonate;

(S)-2- 4-(3-Fluorobenzyloxy)benzyl!amino-N,N-dimethyl propionamide,methanesulfonate;

(S)-2- 4-(2-Chlorobenzyloxy)benzyl!amino-N,N-dimethyl propionamide,methanesulfonate;

(S)-2- 4-(2-Chlorobenzyloxy)benzyl!amino-3-hydroxy-N,N-dimethylpropionamide, methanesulfonate: and

(S)-2-(4-Benzyloxybenzyl)amino-N,N-dimethylpropionamide,methanesulfonate.

EXAMPLE 5

8 g (0.026 tool) of 4-(3-chlorobenzyl)oxybenzyl!aminoacetamide aredissolved in methanol (100 ml) and 3.6 g (0.026 mol) of anhydrouspotassium carbonate are added to the solution. Methyl iodide (3 ml;0.050 tool)is dropped into the mixture which is stirred for 2 hours atroom temperature and then evaporated to dryness. The crude residue ischromatographed on silica gel(eluant: chloroform/methanol; 95/5).

4.25 g (51.3%) of 2-N-(4-(3-chlorobenzyloxy)benzyl)-N-methyl!aminoacetamide are obtained(m.p. 108°-111° C.).

Analogously the following compounds can be obtained and, if required,salified with a suitable acidic agent:

(S)-2- N-(4-Benzyloxybenzyl)-N-methyl!amino-N-methyl propionamide; m.p.80°-82.5° C.;

(S)-2-N-(4-(3-Chlorobenzyloxy)benzyl)-N-methyl!amino-3-hydroxy-N-methylpropionamide,fumarate m.p. 87.5°-95° C. (dec);

(S)-2-N-(4-Benzyloxybenzyl)-N-methyl!amino-3-hydroxy-N-methylpropionamide;m.p. 75°-78° C.;

(S)-2-N-(4-(3-Chlorobenzyloxy)benzyl)-N-methyl!amino-N-methylpropionamide,oxalate m.p. 75°-85° C.(1.54% water);

(S)-N- (4-Benzyloxybenzyl)-N-methyl!aminopropionamide m.p. 102°-104° C.;and

(S)-2- N-(4-(3-Chlorobenzyloxy)benzyl)-N-methyl!aminopropionamide m.p.81°-84° C.

EXAMPLE 6

Tablets, each weighing 300 mg and containing 100 mg of active substancecan be manufacturated as follows:

    ______________________________________    Compositions (for 5000 tablets)    ______________________________________     4-(3-Chlorobenzyl)oxybenzyl!                             500 g    aminoacetamide hydrochloride    Lactose                  710 g    Corn starch              237.5 g    Talc powder              37.5 g    Magnesium stearate       15 g    ______________________________________

2- 4-(3-chlorobenzyloxy)benzyl!aminoacetamide hydrochloride, lactose andhalf of the corn starch are mixed; the mixture is then forced through asieve of 0.5 mm openings. Corn starch (18 g) is suspended in warm water(180 ml).

The resulting paste is used to granulate the powder. The granules aredried, comminuted on a sieve of sieve size 1.4 mm, then the remainingquantity of starch, talc and magnesium is added, carefully mixed, andprocessed into tablets.

EXAMPLE 7

Tablets, each weighing 300 mg and containing 100 mg of the activesubstance can be manufactured as follows:

    ______________________________________    Compositions (for 500 tablets)    ______________________________________    (S)- 2-(4-Benzylbenzyl)amino-                             500 g    propionamide, methanesulfonate    Lactose                  710 g    Corn starch              237.5 g    Talc powder              37.5 g    Magnesium starate        15 g    ______________________________________

(S)-2-(4-Benzylbenzyl)aminopropionamide methanesulfonate, lactose andhalf of the corn starch are mixed; the mixture is then forced through asieve of 0.5 mm openings. Corn starch (18 g) is suspended in warm water(180 ml).

The resulting paste is used to granulate the powder. The granules aredried, comminuted on a sieve size 1.4 mm, then the remaining quantity ofstarch, talc and magnesium is added, carefully mixed, and processed intotablets.

We claim:
 1. A method of treating a patient with Parkinson's disease, depression, involuntary spasm, brain ischemia or inducing hypnosis, which method comprises administering to the patient a therapeutically effective amount of a compound of formula (I) ##STR14## wherein R is selected from the group consisting of C₁ -C₈ alkyl, C₃ -C₈ cycloalkyl, furyl, thienyl, pyridyl and phenyl, the phenyl ring being unsubstituted or substituted by 1 to 4 substituents independently chosen from the group consisting of halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy and trifluoromethyl;A is --(CH₂)_(m) -- or --(CH₂)_(p) --X--(CH₂)_(q) --, wherein m is an integer of 1 to 4, one of p and q is zero and the other is zero or an integer of 1 to 4, and X is selected from the group consisting of --O--, --S-- and --NR₄ -- in which R₄ is hydrogen or C₁ -C₄ alkyl; n is zero or 1; each of R₁ and R₂, independently, is hydrogen or C₁ -C₄ alkyl; R₃ is selected from the group consisting of hydrogen and C₁ -C₄ alkyl which is unsubstituted or substituted by hydroxy or by a phenyl ring optionally substituted by 1 to 4 substituents independently chosen from the group consisting of halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy and trifluoromethyl; R'₃ is hydrogen; or R₃ and R'₃ taken together with the adjacent carbon atom form a C₃ -C₆ cycloalkyl ring; each of R₅ and R₆, independently, is hydrogen or C₁ -C₆ alkyl; and wherein when R is C₁ -C₈ alkyl, then A is a --(CH₂)_(p) --X--(CH₂)_(q) -- group in which p and q are both zero and X is as defined above; or a pharmaceutically acceptable salt thereof.
 2. A method according to claim 1 wherein, in formula (I),R is a phenyl ring unsubstituted or substituted by one or two substituents independently chosen from the group consisting of from halogen, C₁ -C₄ alkyl and trifluoromethyl; A is --(CH₂)_(m) -- or --(CH₂)_(p) --X--(CH₂)_(q) --, wherein m is 1 or 2, one of p and q is zero and the other is zero, 1, 2 or 3, and X is selected from the group consisting of --O--, --S-- and --NH--; n is zero or 1; each of R₁ and R₂ independently, is hydrogen or C₁ -C₄ alkyl; R₃ is hydrogen or C₁ -C₄ alkyl optionally substituted by hydroxy; R'₃ is hydrogen; and each of R₅ and R₆ is independently hydrogen or C₁ -C₄ alkyl.
 3. A method according to claim 1, wherein in formula (I),R is a phenyl ring unsubstituted or substituted by halogen; A is --(CH₂)_(m) -- or --(CH₂)_(p) --X--(CH₂)_(q) -- wherein m is 1 or 2; one of p and q is zero and the other is zero, 1, 2 or 3 and X is selected from the group consisting of --O--, --S-- and --NH--; n is zero; R₁ is hydrogen; R₂ is hydrogen or C₁ -C₂ alkyl; R₃ is hydrogen or C₁ -C₂ alkyl optionally substituted by hydroxy; R'₃ is hydrogen; and each of R₅ and R₆ independently is hydrogen or C₁ -C₄ alkyl.
 4. A method according to claim 1, wherein the said compound of formula (I) is selected from the group consisting of:2-(4-benzyloxybenzyl)aminopropionamide; 2- 4-(2-chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide; 2- 4-(2-chlorobenzyloxy)benzyl!aminopropionamide; 2- 4-(3-fluorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide; 2-(4-benzylaminobenzyl)aminopropionamide; 2- 4-(3-fluorobenzyloxy)benzyl!aminopropionamide; 2- 4-(2-fluorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide; 2- N-(4-benzylbenzyl)-N-methyl!aminopropionamide; 2- 4-(3-chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide; 2-(4-benzyloxybenzyl)amino-3-hydroxy-N-methylpropionamide; 2- 4-(3-chlorobenzyloxy)benzyl!aminopropionamide; 2- N- 4-(3-chlorobenzyloxy)benzyl!-N-methyl!aminoacetamide; 2- 4-(3-chlorobenzyloxy)benzyl!amino-N-methylacetamide; 2-(4-phenyloxybenzyl)amino-3-hydroxy-N-methylpropionamide; 2-(4-benzylbenzyl)aminopropionamide; 2- 4-(2-phenylethyl)benzyl!aminopropionamide; 2-(4-phenyloxymethylbenzyl)aminopropionamide; 2-(4-benzylthiobenzyl)aminopropionamide; 2- 4-(2-chlorobenzyloxy)benzyl!amino-N-methylpropionamide; 2-(4-benzyloxybenzyl)amino-N-methylpropionamide; 2- 4-(3-chlorobenzyloxy)benzyl!aminoacetamide; 2- 4-(3-phenylpropyloxy)benzyl!aminopropionamide; (4-benzyloxybenzyl)aminoacetamide; 4-(3-chlorobenzyloxy)-α-methyl-benzyl!aminoacetamide; 2- 4-(3-chlorobenzyloxy)benzyl!amino-3-hydroxypropionamide; 2- 4-(3-chlorobenzyloxy)benzyl!amino-N-methylpropionamide; 2- 4-(3-methoxybenzyloxy)benzyl!amino-3-hydroxy-N-methyl propionamide; 2- 4-(4-chlorobenzyloxy)benzyl!amino-3-hydroxy-N-methyl propionamide; 1- (4-benzyloxybenzyl)amino!cyclopentane-1-N-methylcarboxamide; 2-(4-benzyloxybenzyl)amino-N-methylacetamide; 1- (4-benzyloxybenzyl)amino!cyclopropane-1-N-methylcarboxamide; 1- (4-benzyloxybenzyl)amino!cyclopentane-1-carboxamide; 2-(4-benzyloxybenzyl)amino-3-methyl-N-methylbutanamide; 2-(4-benzyloxybenzyl)amino-3-phenyl-N-methylpropionamide; 1- (4-benzyloxybenzyl)amino!cyclopropane-1-carboxamide; 2-(4-benzyloxybenzyl)amino-3-hydroxy-N-methyl-butanamide; 2-(4-benzyloxybenzyl)amino-4-methyl-N-methylpentanamide; 2-(4-benzyloxybenzyl)amino-3-hydroxy-propionamide; 2- 4-(2-methylbenzyloxy)benzyl!amino-3-hydroxy-N-methyl propionamide; 2- 4-(3-methylbenzyloxy)benzyl!amino-3-hydroxy-N-methyl propionamide; 2- 4-(3-trifluoromethylbenzyloxy)benzyl!amino-3-hydroxy-N-4-methylpropionamide; 2- 4-(2-trifluoromethylbenzyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide; 2-(4-phenyloxybenzyl)aminopropionamide; 2-(4-benzylbenzyl)amino-3-hydroxy-N-methylpropionamide; 2-(4-phenylethyloxybenzyl)aminopropionamide; 2-(4-benzylthiobenzyl)amino-3-hydroxy-N-methylpropionamide; 2-(4-phenylethylbenzyl)amino-3-hydroxy-N-methyl-propionamide; 2- 4-(2-phenylethyloxy)benzyl!amino-3-hydroxy-N-methylpropionamide; 2- 4-(2-fluorobenzyloxy)benzyl!aminopropionamide; 2-(4-phenyloxymethylbenzyl)amino-3-hydroxy-N-methyl-propionamide; 2-(4-benzylaminobenzyl)amino-3-hydroxy-N-methyl-propionamide; 2-(4-benzyloxyphenethyl)aminopropionamide; 2- 4-(2-chlorobenzyloxy)phenethyl!aminopropionamide; 2- 4-(3-chlorobenzyloxy)-α-methyl-benzyl!aminopropionamide; 2- (4-benzyl)-α-methyl-benzyl!aminopropionamide, 2-(4-benzyloxybenzyl)aminobutanamide; 2-(2-benzyloxybenzyl)aminopropionamide; 2-(3-benzyloxybenzyl)aminopropionamide; 2-(4-cyclohexylmethylaminobenzyl)aminopropionamide; 2-(4-cyclopropylmethylaminobenzyl)aminopropionamide; 2-(4-phenylaminomethylbenzyl)aminopropionamide; 2- 4-(3-furfuryloxy)benzyl!aminopropionamide; 2- 4-(2-furfuryloxy)benzyl!aminopropionamide; 2- 4-(3-pyridyl)methyloxybenzyl!aminopropionamide; 2- 4-(2-pyridyl)methyloxybenzyl!aminopropionamide; 2- 4-(4-pyridyl)methyloxybenzyl!aminopropionamide; 2- 4-(3-thienyloxy)benzyl!aminopropionamide; 2- 4-(2-thienyloxy)benzyl!aminopropionamide; 2- N-(4-benzyloxybenzyl)-N-methyl!amino-3-hydroxy-N-methyl propionamide; 2- N-(4-phenyloxymethylbenzyl)-N-methyl!aminopropionamide; 2- N-(4-benzylethylbenzyl)-N-methyl!aminopropionamide; 2- N-(4-benzylbenzyl)-N-methyl!amino-3-hydroxy-N-methylpropionamide; 2- N-(4-benzylthiobenzyl)-N-methyl!aminopropionamide; 2- N-(4-benzylaminobenzyl)-N-methyl!aminopropionamide; 2- N-(4-(2-chlorobenzyloxy)benzyl)-N-methyl!amino-3-hydroxy-N-methylpropionamide; 2- N-(4-(3-fluorobenzyloxy)benzyl)-N-methyl!amino-3-hydroxy-N-methylpropionamide; 2- N-(4-(2-fluorobenzyloxy)benzyl-N-methyl!amino-3-hydroxy-N-methylpropionamide; 2- N-(4-(3-fluorobenzyloxy)benzyl-N-methyl!amino-propionamide; 2- N-(4-(2-chlorobenzyloxy)benzyl-N-methyl!amino propionamide; 4-(3-chlorobenzyloxy)phenylethyl!aminoacetamide; 4-(3-chlorobenzyloxy)-α-methyl-benzyl!aminoacetamide; 2- (4-benzyl)phenylethyl!aminoacetamide; 2- 2-(4-benzylamino)phenylethyl!aminoacetamide; 2-(4-benzyloxybenzyl)amino-N,N-dimethylacetamide; 2-(4-benzyloxybenzyl)amino-3-hydroxy-N,N-dimethylpropionamide; 2-(4-benzylbenzyl)amino-N,N-dimethylacetamide; 2-(4-benzylaminobenzyl)amino-N,N-dimethylacetamide; 2- 4-(2-chlorobenzyloxy)benzyl!amino-3-hydroxy-N,N-dimethylpropionamide; 2- 4-(3-fluorobenzyloxy)benzyl!amino-3-hydroxy-N,N-dimethylpropionamide; 2- 4-(2-fluorobenzyloxy)benzyl!amino-3-hydroxy-N,N-dimethylpropionamide; 2- 4-(3-fluorobenzyloxy)benzyl!amino-N,N-dimethyl propionamide; 2- 4-(2-chlorobenzyloxy)benzyl!amino-N,N-dimethyl propionamide; 2- 4-(2-chlorobenzyloxy)benzyl!amino-3-hydroxy-N,N-dimethyl propionamide; 4-(3-chlorobenzyl)oxybenzyl!amino-N,N-dimethylacetamide; 2-(4-benzyloxybenzyl)amino-N,N-dimethylpropionamide; 2- N-(4-benzyloxybenzyl)-N-methyl!amino-N-methyl propionamide, 2- N-(4-(3-chlorobenzyl)oxybenzyl)-N-methyl!amino-3-hydroxy-N-methylpropionamide; 2- N-(4-(3-chlorobenzyl)oxybenzyl)-N-methyl!amino-N-methylpropionamide; N- (4-benzyloxybenzyl)-N-methyl!aminopropionamide; 2- N-(4-(3-chlorobenzyl)oxybenzyl)-N-methyl!aminopropionamide;as single (S) or (R) isomers or as a mixture thereof, and the pharmaceutically acceptable salts thereof.
 5. A method according to claim 1 wherein the pharmaceutically acceptable salt of the compound of formula (I) is an acid addition salt with hydrochloric acid or methanesulphonic acid. 